causes lethal pneumonia following infection of the lungs by targeting macrophages for intracellular replication; however, macrophages stimulated with interferon gamma (IFN-γ) can resist infection We therefore hypothesized that the protective effect of IFN-γ against requires macrophages receptive to stimulation. We found that the lethality of pulmonary LVS infection was exacerbated under conditions of alveolar macrophage depletion and in mice with a macrophage-specific defect in IFN-γ signaling (termed mice with macrophages insensitive to IFN-γ [MIIG mice]). We previously found that treatment with exogenous interleukin 12 (IL-12) protects against infection; this protection was lost in MIIG mice. MIIG mice also exhibited reduced neutrophil recruitment to the lungs following infection. Systemic neutrophil depletion was found to render wild-type mice highly sensitive to respiratory infection, and depletion beginning at 3 days postinfection led to more pronounced sensitivity than depletion beginning prior to infection. Furthermore, IL-12-mediated protection required NADPH oxidase activity. These results indicate that lung macrophages serve a critical protective role in respiratory LVS infection. Macrophages require IFN-γ signaling to mediate protection, which ultimately results in recruitment of neutrophils to further aid in survival from infection.